Colorectal cancer (CRC) is the third most prevalent type of cancer diagnosed each year and CRC patients have the second highest mortality rate, worldwide. Standard of care treatments for CRC is largely ineffective against metastatic CRC (mCRC), which has an 11% 5-year overall survival rate. Aberrant T-Cell Factor (TCF) transcription is a major driver of tumor progression to mCRC. Therapeutic development directly targeting the inhibition of TCF-transcription of genes associated with mCRC may be an effective therapeutic strategy for mCRC, and currently no such therapies are clinically approved. Using a cohort of ~600 CRC patient tumor samples (GEOdataset (GSE40967) and CU AMC GI tissue bank), we have identified an oncogene, known as CHD1L, to be linked as a driver of mCRC and patient poor prognosis. We have characterized CHD1L to be a required component of TCF-transcription during malignant gene expression. We hypothesize that CHD1L is a molecular target that functions as a DNA binding factor for the TCF-transcription complex, and CHD1L is specifically recruited to activate mesenchymal genes and other genes associated with mCRC. Currently there are no known inhibitors of CHD1L. Thus, we conducted HTS drug discovery targeting recombinant CHD1L ATPase to identify the first-in-class inhibitors of CHD1L. In Aim 1 we will validate these CHD1L inhibitors as lead drugs using a hit-to-lead schema in sequence. In Aim 2 we will conduct drug design and medicinal chemistry based on a validated lead CHD1L inhibitor pharmacophore. In Aim 3 we will prioritize 15 lead CHD1L inhibitors for in vivo pharmacology, including pharmacokinetics, pharmacodynamics, and efficacy in patient derived xenografts. This research will lead to a diversity of novel CHD1L inhibitors that can be developed as molecular probes or potential therapeutics that would be expected to impact our understanding and treatment of mCRC.